PROJECT SUMMARY/ABSTRACT The applicant's long-term objective is to develop a research program focusing on understanding biological mechanisms underpinning externalizing behaviors, including those associated with PTSD, in order to facilitate the development of improved strategies to reduce these behaviors. This is consistent with the NIMH's mission to reduce the burden of mental illness. The applicant's medium-term objective is to become an independent, NIH-funded investigator and a recognized expert in neural and endocrine mechanisms implicated in trauma and aggression. The applicant will accomplish this by i) deepening an existing competency in fMRI with advanced functional connectivity methods; ii) broadening an existing competency in conducting clinical research by gaining experience working in a residential treatment facility and by acquiring training in PTSD assessment techniques; and iii) gaining new competency in endocrinology research. PTSD effects an estimated > 21 million Americans and >30% of PTSD patients do not respond to treatment. PTSD may manifest in the brain as increased neural response to threat cues and disrupted neural responses during emotion regulation. Evidence of PTSD may also present in the body; i.e., as high levels of testosterone. The link between testosterone, neural responses and PTSD is poorly understood. A better understanding of the biological mechanisms underpinning PTSD would likely facilitate the development of improved interventions. Thus, this proposal aims to (i) determine the extent to which testosterone responsiveness modulates response to threat cues in youth with PTSD and (ii) determine the extent to which testosterone responsiveness modulates emotion regulation deficits in youth with PTSD. The applicant proposes to accomplish these aims by recruiting 38 adolescent patients with PTSD and 38 comparison adolescents (aged 14-17; half male; controlling for pubertal status) from a large residential treatment program. A counter-balanced repeated-measures design will be employed where participants will complete an fMRI paradigm designed to assess response to threat and emotion regulation following a testosterone manipulation. Pilot data indicates that a testosterone response can be non-invasively elicited by a social challenge paradigm. Participants will complete the fMRI task following this challenge paradigm or following a paradigm designed to reduce T levels. It is anticipated that the proposed study will show the extent to which an increase in T is associated with an increased responsiveness to emotional stimuli and reduced emotion regulation in youth with PTSD. As current intervention strategies for pediatric PTSD do not consider the role of T, these data will be important in the development of novel treatment modalities. The proposed research would take place at Boys Town, Omaha, NE and Iowa State Univ. Participants will be drawn from the approximately 500 youth in residential treatment at Boys Town and scanned using the on- site dedicated research scanner, while the endocrine research would take place at Iowa State.